The p90 ribosomal S6 kinase (RSK) family is comprised of four isoforms, RSK1, RSK2, RSK3 and RSK4. These isoforms are pivotal for transmitting cell signalling from cell surface receptors such as growth factors, hormones, and cytokines. RSK1 and RSK2 are the isoforms most common to cancer where they control cell growth, invasion and the suppression of apoptosis. RSK3 is not commonly expressed in cancer, however, it has been associated with drug resistance as have RSK1 and RSK2. RSK4 is not commonly expressed in cancer. The RSK family is also fundamental to inflammation, diabetes and heart disease.
In the field of oncology, RSK inhibitors provide an opportunity for targeted therapy to improve the treatment of cancer. Inhibiting RSK also affords an opportunity to overcome drug resistance through multiple mechanisms including the elimination of cancer stem cells (CSC) or tumor-initiating cells (TIC). RSK inhibitors can reportedly overcome resistance to targeted therapies such as Herceptin, Gefitinib, and Enzalutamide. RSK inhibitors can also be used to augment resistance to microtubule cytotoxics such as paclitaxel.
There are many types of cancers associated with RSK activity, including, but not limited to, breast, prostate, lung, brain, blood, skin, bone, and ovarian cancers. In the field of breast and prostate cancer research, RSK inhibitors have been shown to block hormone signalling. As with many types of cancer, those that arise in the breast are genetically diverse and as such have been categorized into three main types: Type 1, which is hormone positive expressing the estrogen and progresterone receptors (ER and PR respectively); Type 2, which is Her-2 positive; and Type 3, which is triple-negative as the cancer cells lack ER, PR and Her-2 receptors. The triple-negative breast cancer (TNBC) is currently considered the most aggressive and is associated with the worst outcomes for patients. It constitutes 15-25% of all breast cancers and is more common in younger women. Women with mutations in the breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2) are more likely to develop TNBC then the other types of breast cancer.
Accordingly, there is a need for small molecule inhibitors of RSK which are useful in treating diseases and conditions associated with the activity of RSK, such as cancer.